基因组学 - 首次评估与Titin缩小变体相关的心脏病
Christopher M Haggerty1, Scott M Damrauer2,3, Michael G Levin2
1Geisinger, Danville, PA (C.M.H., D.J.C., A.M.G., D.N.H., Y.H., M.A.K., H.L.K., J.B.L., Z.N., T.N.P., A.P., D.T.S., R.C.S., A.C.S., M.F.M., B.K.F.).
Circulation
|June 21, 2019
概括
蒂基因 (TTNtvs) 的缩减变异与欧洲人扩张性心肌病 (DCM) 有关,但非非洲血统的个体没有. 这些变异与心脏功能减弱和心力衰竭风险增加有关,即使没有DCM诊断.
科学领域:
- 遗传学
- 心脏病学
- 基因组学
背景情况:
- 在被诊断为特异性扩展性心肌病 (DCM) 的个体中经常观察到Titin基因 (TTNtvs) 的缩减变异.
- 对TTNtvs在不同临床场景中的影响和遗传祖先修饰剂的影响进行全面的基因组学第一评估是缺乏的.
研究的目的:
- 在大型健康计划中对TTNtvs进行基因组学首次评估.
- 评估TTNtvs与DCM和心脏功能的相关性.
- 调查遗传祖先在修改这些关联中的作用.
主要方法:
- 分析了来自Geisinger和PennMedicine BioBank的超过71,000名个体的整个外基因组测序数据.
- 选择了具有高心表达异位体 (hiPSI) 的TTNtvs个体.
- 链接电子健康记录和来自杰克逊心脏研究的数据被用来评估与诊断,心声测量和遗传血统的关联.
主要成果:
- 在1. 2% (PennMedicine) 和0. 6% (Geisinger) 个体中发现了 hiPSI TTNtvs.
- 在欧洲血统的个体中,hiPSI TTNtvs显著增加了DCM的几率 (OR:18. 7 PennMedicine, 10. 8 Geisinger).
- 在非洲祖先的个体中没有发现hiPSI TTNtvs和DCM之间的关联 (OR: 1. 8).
- 在患有DCM的欧洲血统个体中,hiPSI TTNtv携带者表现出较低的喷射分数 (β=-12%) 和增加的腹腔直径 (β=0. 65厘米).
- 在没有DCM的盖辛格队列携带者中,hiPSI TTNtvs与心房动 (OR: 2. 4),心力衰竭 (OR: 3. 8) 和较低的射出分数 (β=-3. 4%) 相关.
结论:
- 欧洲血统的hiPSI TTNtv携带者表现出异常的心脏表型,包括减少排气分数,无论临床心肌病诊断如何.
- 即使考虑到心肌病,也观察到与心律失常 (如心房) 的相关性.
- 在非洲血统的个体中,没有发现hiPSI TTNtvs和DCM之间的关联.
- 临床识别hiPSI TTNtv携带者可以为患者的治疗策略提供信息.
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